Abstract
Vascular endothelial growth factor receptor 2 (VEGFR2) is an attractive therapeutic target in solid malignancies due to its central role in tumor angiogenesis. Ramucirumab (Cyramza®, LY3009806) is a human monoclonal antibody specific for VEGFR2 approved for several adult indications and currently in a phase 1 clinical trial for pediatric patients with solid tumors (NCT02564198). Here, we evaluated ramucirumab in vitro and the anti-murine VEGFR2 antibody DC101 in vivo with or without chemotherapy across a range of pediatric cancer models. Ramucirumab abrogated in vitro endothelial cord formation driven by cancer cell lines representing multiple pediatric histologies; this response was independent of the origin of the tumor cell-line. Several pediatric cancer mouse models responded to single agent DC101-mediated VEGFR2 inhibition with tumor growth delay. Preclinical stable disease and partial xenograft regressions were observed in mouse models of Ewing’s sarcoma, synovial sarcoma, neuroblastoma, and desmoplastic small round cell tumor treated with DC101 and cytotoxic chemotherapy. In contrast, DC101 treatment in osteosarcoma models had limited efficacy alone or in combination with chemotherapeutics. Our data indicate differential efficacy of targeting the VEGFR2 pathway in pediatric models and support the continued evaluation of VEGFR2 inhibition in combination with cytotoxic chemotherapy in multiple pediatric indications.
Highlights
Though survival rates for pediatric cancer patients have improved dramatically since the early 1960s, cancer remains the leading cause of disease-related death in children and adolescents [1]
To first establish the expression patterns of Vascular endothelial growth factor receptor 2 (VEGFR2) and its associated ligands in our pediatric cancer models, we profiled a panel of 11 pediatric cancer cell lines representing neuroblastoma (IMR-32, KELLY, SH-SY5Y), retinoblastoma (Y79), osteosarcoma (HOS, Saos-2, SJSA1), rhabdomyosarcoma (SJCRH30 [alveolar RMS], RD [embryonal RMS]), malignant rhabdoid tumor (A-204), and Ewing’s sarcoma (RD-ES) for VEGFR2 protein expression (Figure 1A)
VEGFR2 was absent from the majority of cancer cell lines and detected in only 3 out of the 11 cell lines (KELLY, SJCRH30, and RD) at much lower levels than the vascular endothelial growth factor A (VEGF-A)-stimulated endothelial colony forming cell (ECFC) control
Summary
Though survival rates for pediatric cancer patients have improved dramatically since the early 1960s, cancer remains the leading cause of disease-related death in children and adolescents [1]. Aberrant activation of VEGFR2 on endothelial cells by tumor cellsecreted VEGF-A drives angiogenesis, the development of new blood vessels from existing vessels. This new blood vessel growth supports tumor progression, local invasion, and metastasis [8, 9]. Preclinical and clinical studies have demonstrated that small molecule inhibitors of the VEGF pathway have anti-tumor activity in some pediatric malignancies; it is still unclear which pediatric indications may receive the most benefit from anti-VEGFR2 therapy, either alone or in combination with chemotherapy [14,15,16,17,18]. We tested ramucirumab or the anti-mouse VEGFR2 antibody DC101 (a ramucirumab surrogate for in vivo studies) in multiple pediatric cancer cell lines and xenograft mouse models with the goal of identifying specific pediatric indications that may respond to ramucirumab-mediated VEGFR2 inhibition
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
